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Aiding in the diagnosis of hereditary hemorrhagic telangiectasia, types 1 and 2
Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant vascular dysplasia characterized by the presence of arteriovenous malformations (AVM) of the skin, mucosa, and viscera. Small AVMs, or telangiectasias, develop predominantly on the face, oral cavity, and/or hands, and spontaneous, recurrent epistaxis (nosebleed) is a common presenting sign. Symptomatic telangiectasias occur in the gastrointestinal tract of about 30% of HHT patients. Additional serious complications associated with HHT include transient ischemic attacks, embolic stroke, heart failure, cerebral abscess, massive hemoptysis, massive hemothorax, seizure, and cerebral hemorrhage. These complications are a result of larger AVMs, which are most commonly pulmonary, hepatic, or cerebral in origin, and occur in approximately 30%, 40%, and 10% of individuals with HHT, respectively.
HHT is inherited in an autosomal dominant manner; most individuals have an affected parent. HHT occurs with wide ethnic and geographic distribution, and is significantly more frequent than formerly thought. It is most common in Caucasians, but it occasionally occurs in Asians, Africans, and individuals of Middle Eastern descent. The overall incidence of HHT in North America is estimated to be between 1 in 5,000 and 1 in 10,000. Penetrance seems to be age related, with increased manifestations occurring over one's lifetime. For example, approximately 50% of diagnosed individuals report having nosebleeds by age 10 years, and 80% to 90% by age 21 years. As many as 90% to 95% of affected individuals eventually develop recurrent epistaxis.
Two genes are most commonly associated with HHT: the endoglin gene (ENG), containing 15 exons and located on chromosome 9 at band q34; and the activin A receptor, type II-like 1 gene (ACVRL1 or ALK1), containing 10 exons and located on chromosome 12 at band q1. Mutations in these genes occur in about 80% of individuals with HHT. ENG and ACVRL1 encode for membrane glycoproteins involved in transforming growth factor-beta signaling related to vascular integrity. Mutations in ENG are associated with HHT type 1 (HHT1), which has been reported to have a higher incidence of pulmonary AVMs, whereas ACVRL1 mutations occur in HHT type 2 (HHT2), which has been reported to have a higher incidence of hepatic AVMs. It has been suggested that HHT1 has a more severe phenotype compared to HHT2.
The majority of mutations in ENG and ACVRL1 are point mutations, which are detectable by sequencing. Sequencing of ENG and ACVRL1 provides for a detection rate of approximately 60% to 80% of mutations involved in HHT. Approximately 10% of ENG and ACVRL1 mutations are large genomic deletions and duplications (also known as dosage alterations), which are not detectable by sequencing, but are detectable by methods such as multiplex ligation-dependent probe amplification (MLPA).
HHT is phenotypically heterogeneous both between families and amongst affected members of the same family. Furthermore, complications associated with HHT have variable ranges of age of onset. Thus, HHT can be diagnostically challenging. Genetic testing for ENG and ACVRL1 mutations allows for the confirmation of a suspected genetic disease. Confirmation of HHT diagnosis will allow for proper treatment and management of the disease, preconception/prenatal counseling, and family counseling. In addition, it has been estimated that genetic screening of suspected HHT individuals and their families is more economically effective than conventional clinical screening.(1)
An interpretive report will be provided.
An interpretive report will be provided.
Blood samples may contain donor DNA if obtained from patients who received heterologous blood transfusions or allogeneic blood or marrow transplantation. Results from samples obtained under these circumstances may not accurately reflect the recipient’s genotype. For individuals who have received blood transfusions, the genotype usually reverts to that of the recipient within 6 weeks. For individuals who have received allogeneic blood or marrow transplantation, a pretransplant DNA specimen is recommended for testing.
Absence of a mutation does not preclude the diagnosis of hereditary hemorrhagic telangiectasia (HHT) unless a specific mutation has already been identified in an affected family member. Mutations in ACVRL1 and ENG occur in approximately 80% of individuals with clinically-defined HHT.
This method will not detect mutations that occur deep in the introns and in the regulatory regions of the gene.
Sometimes a genetic alteration of unknown significance may be identified. In this case, testing of appropriate family members may be useful to determine pathogenicity of the alteration.
Any error in the diagnosis or in the pedigree provided to us, including false paternity, could lead to erroneous interpretation of results.
Rare, undocumented polymorphisms may be present which could lead to false-negative or false-positive results.
Once a mutation has been identified in a family, targeted mutation analysis can be performed in at-risk family members:
-ENGK / Hereditary Hemorrhagic Telangiectasia, ENG Gene, Known Mutation
-ACVK / Hereditary Hemorrhagic Telangiectasia, ACVRL1 Gene, Known Mutation
Or if a duplication or deletion is identified:
-HHTM / Hereditary Hemorrhagic Telangiectasia, ENG and ACVRL1 Large Deletion/Duplication, Molecular Analysis
In addition to disease-related probes, the multiplex ligation-dependent probe amplification technique utilizes probes localized to other chromosomal regions as internal controls. In certain circumstances, these control probes may detect other diseases or conditions for which this test was not specifically intended. Results of the control probes are not normally reported. However, in cases where clinically relevant information is identified, the ordering physician will be informed of the result and provided with recommendations for any appropriate follow-up testing.
1. Cohen J, Faughnan ME, Letarte M, et al: Cost comparison of genetic and clinical screening in families with hereditary hemorrhagic telangiectasia. Am J of Med Genet A 2005 Aug 30;137(2):153-160
2. Sabba C, Pasculli G, Lenato GM, at al: Hereditary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carriers. J Thromb Haemost 2007 Jun;5(6):1149-1157
3. Abdalla SA, Letarte M: Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease.J Med Genet 2006 Feb;43(2):97-110
4. Guttmacher AE, Marchuk DA, White RI Jr: Hereditary hemorrhagic telangiectasia. N Engl J Med 1995 Oct 5;333(14):918-924
5. Bayrak-Toydemir P, Mao R, Lewin S, et al: Hereditary hemorrhagic telangiectasia: an overview of diagnosis and management in the molecular era for clinicians. Genet Med 2004;6:175–191